Diabetes is a major factor in disease rates and mortality. Chronic elevated blood sugar levels cause the following complications that make the body debilitate: renal disease, often requiring dialysis or kidney transplantation; peripheral neuropathy; retinopathy leading to blindness; ulcers of the legs and feet resulting in amputation; fatty liver disease that sometimes develops into cirrhosis; and onset of coronary artery disease and myocardial infarction.
There are two main types of diabetes. Type I, or insulin-dependent diabetes mellitus (IDDM), is caused by autoimmune destruction of insulin-producing beta cells of the pancreatic islets. The disease usually occurs in infancy or puberty. Treatment of the disease consists mainly of injecting insulin several times a day. In order to control the dose of insulin, the blood glucose level is tested several times because excess insulin causes hypoglycemia and results in damage to the brain or other functions.
Type II, or noninsulin-dependent diabetes mellitus (NIDDM), typically develops in adults. NIDDM is associated with glucose-using tissues such as adipose tissue, muscle and liver being resistant to the action of insulin. Initially, pancreatic islet beta cells compensate by releasing excess insulin. The ultimate islet β cell failure results in decompensation and chronic hyperglycemia. Conversely, a moderate islet β cell failure may precede or coincide with peripheral insulin resistance. There are several classes of drugs useful in the treatment of NIDDM: 1) an insulin secretagogue that directly stimulates insulin secretion, but at risk of causing hypoglycemia; 2) a dietary insulin secretagogue that enhances glucose-induced insulin secretion but must be ingested before every meal; 3) biguanide including metformin, which inhibits hepatic glucose uptake (which is greatly elevated in diabetes); 4) insulin sensitizers such as thiazolidinedione derivatives rosiglitazone and pioglitazone, which improve peripheral responsiveness to insulin but have side effects such as weight gain, edema and hepatotoxicity; 5) Insulin injection, often required at the end of NIDDM, when islet β cell is failure under chronic hyperstimulation.
Insulin resistance also occurs without significant hyperglycemia and is commonly associated with atherosclerosis, obesity, hyperlipidemia and essential hypertension. The group of abnormal symptoms consists of “metabolic syndrome” or “insulin resistance syndrome”. Insulin resistance is also associated with fatty liver, which can develop into chronic inflammation (NASH: “nonalcoholic fatty liver”), fibrosis and cirrhosis. In conclusion, insulin resistance including diabetes is the basis for many of the major factors leading to disease rates and mortality in people over 40 years of age.
Despite the variety of drugs mentioned above, diabetes remains a serious public health problem. Therefore, it is necessary to develop a safe and effective therapeutic agent for diabetes and the fatty liver caused thereby.